The proposed research addresses a mission of the National Institute on Aging ? to develop understanding and improve health outcomes of chronic wounds in aging. The goals of the proposed project are to enhance knowledge of chronic venous leg ulcers (CVLUs) and provide evidence-based guidance in the treatment of CVLUs, wounds that cause substantial morbidity, disability, hospitalization, and even mortality among older adults. New therapies for CVLUs are needed because standard topical therapies are often ineffective or yield only short-term healing. Congruent with PA-16-230, Non-healing Ulcerative Wounds in Aging, the project?s interdisciplinary team plans to test an oral nutrient therapy containing the bioactive elements of fish oil to stimulate healing and prevent recurrence of CVLUs. CVLU pathobiology involves venous hypertension and high numbers of activated polymorphonuclear leukocytes (PMNs) in venous circulation and the ulcer microenvironment, where they secrete excessive amounts of proteases that keep ulcers chronically inflamed. Collective data from the team?s previous work support the organizing hypothesis that increasing intake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with oral supplementation will expedite CVLU healing and prevent recurrence by raising levels of EPA+DHA-derived lipid mediators and lowering levels of proinflammatory cytokines, thereby reducing PMN activation systemically and in ulcer microenvironments. The collective outcomes are also expected to relieve CVLU-related pain and improve quality of life (QoL). The randomized, double-blind study proposes to include 248 successive eligible adults ? 60 years of age with CVLUs who continue to receive standard care at two university out-patient wound clinics. Participants will be randomized to 2 groups: 12 weeks of daily oral therapy with EPA+DHA (2.5 g/d of EPA + 0.5 g/d of DHA) or daily oral therapy with placebo. At 0, 4, 8 and 12 weeks, across the 2 groups, the team will pursue three specific aims: Aim 1. Compare levels of EPA+DHA-derived lipid mediators, and inflammatory cytokines in blood and CVLU fluid; Subaim 1a. Compare inflammatory cytokine gene expression by PMNs in blood; Aim 2. Compare PMN activation in blood and CVLU fluid, and PMN-derived protease levels in CVLU fluid; Aim 3. Compare reduction in wound area, controlling for factors known to affect healing, and determine relationships with lipid mediators, cytokines and PMN activation. Subaim 3a. Compare frequency of CVLU recurrence and levels of study variables in blood between 2 subgroups within the EPA+DHA group with healed CVLUs (after 3 additional months of EPA+DHA therapy versus placebo therapy beyond Week 12). Subaim 3b. Compare the symptom of pain at all time points and QoL at first and last time points across the 2 groups and 2 subgroups. The findings are expected to lead to a new low-risk adjunct oral therapy to target and reduce excessive PMN activation in CVLU patients. As such, the therapy is expected to stimulate healing of CVLUs in aging, deter recurrence and improve QoL.